Cutoff Point Separating Affected and Unaffected Familial Hypercholesterolemic Patients Validated by LDL-receptor Gene Mutants

Abstract

Familial hypercholesterolemia (FH) results from low-density lipoprotein (LDL) receptor gene mutations. Heterozygotes have twice normal LDL-cholesterol concentrations in early childhood, and experience early myocardial infarction. We demonstrated bimodal cholesterol frequency distributions, independently confirming existence of an identifiable hypercholesterolemic subpopulation. We assayed blood lipids in 181 FH patients genetically diagnosed and 100 unaffected relatives. Receiver operating characteristics curves were constructed. Total cholesterol and LDL-cholesterol concentrations showed bimodality. A total cholesterol cutoff of 225 mg/dl produced results agreeing with DNA testing (specificity, 98.5%; sensitivity, 99.4%). An LDL-cholesterol cutoff of 161-163 mg/dl produced 98.5% specificity and 98.3% sensitivity. Areas under curves were 0.9826 ± ± ± ± ± 0.0058 for total cholesterol, and 0.9852 ± ± ± ± ± 0.0043 for LDLcholesterol. In conclusion, we define total cholesterol and LDL-cholesterol levels of 225 and 160 mg/dl, respectively, as cutoff points of normal subjects and FH patients. J Atheroscler Thromb, 2005; 12: 35-40.

Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: a systematic review and economic evaluation.

“…Of the 15 studies, three (four reports) reported Elucigene FH20, [36][37][38] five (six reports) evaluated LIPOchip, [39][40][41][42][43] four reported LDL-C compared with genetic analysis [44][45][46][47] and three reported ageand gender-specific LDL-C for cascade testing of relatives. [48][49][50] We did not identify any studies reporting a combination of the index tests, that is Elucigene FH20 and LIPOchip.…”

“…49 In studies reporting cascade tests through targeted sequencing the sample size of relatives ranged from 27 relatives (from 104 index cases) 38 to 1034 relatives (from 591 index cases). 50 In the study by Lee and colleagues 48 all included relatives were heterozygous FH (coming from homozygous FH index cases), whereas in the study by Mabuchi and colleagues 46 none was homozygous. The rest of the studies did not report on the status of FH patients.…”

“…In the studies by Taylor and colleagues, 37 Damgaard and colleagues, 45 Mabuchi and colleagues, 46 and Tejedor and colleagues 43 the participants were all adults. In the study by Wiegman and colleagues 50 the participants were children.…”

“…In the study by Starr and colleagues, clinically diagnosed index cases based on the Dutch criteria (the Netherlands) and a combination of lipid levels, clinical characteristics and family history (Norway and Denmark) were included, whereas the study by Mabuchi and colleagues 46 included clinically diagnosed index cases based on TC (≥ 5.9 mmol/l and < 12.9 mmol/l) with tendon xanthomata or primary hypercholesterolaemia with/without tendon xanthomata in a family with FH patients among first-degree relatives. The study by Wiegman and colleagues 50 recruited relatives of index cases with a clinical diagnosis of FH based on the MedPed criteria or from a genetic diagnosis.…”

“…Eight studies reported diagnostic accuracy in index cases only, 36,[39][40][41][42][43][44]46 whereas four 37,38,45,47 reported this information both for index cases and for cascade testing of relatives, with the remaining three studies [48][49][50] reporting test performance for cascade testing of relatives only. In studies reporting cascade testing of relatives these were all first-degree relatives apart from the two studies by Damgaard and colleagues 45 and Lee and colleagues,48 in which this information was not specified.…”